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Mechanism of Induction of Gastrointestinal Toxicity in the Mouse by 5-Fluorouracil, 5-Fluorouridine, and 5-Fluoro-2'-deoxyuridine¹

Department of Biochemical and Clinical Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee 38101

This study was designed to determine the mechanism by which three fluorinated pyrimidines induce gastrointestinal toxicity in the mouse. Two mechanisms were considered: (a) incorporation of the fluorinated analog into RNA; and (b) inhibition of the biosynthesis of thymidine 5'-monophosphate de novo through conversion of the administered agent to 5-fluoro-2'-deoxyuridine monophosphate (FdUMP).

After a single administration, the 50% lethal dose levels for 5-fluorouridine (FUrd), 5-fluorouracil (FUra), and 5-fluoro-2'-deoxyuridine (FdUrd) were approximately 160, 260, and 1400 mg/kg (0.61, 2.0, and 5.7 mmol/kg), respectively. Dose levels of FdUrd that blocked the incorporation of [³H]deoxyuridine into DNA did not inhibit the incorporation of either [³H]deoxyguanosine or [³H]thymidine ([³H]dThd) into gastrointestinal tissues. The inhibition-versus-dose curves for the utilization of [³H]deoxyguanosine and [³H]dThd are similar after treatment with FdUrd. Utilization of [³H]dThd is depressed by FUrd, FUra, and FdUrd in a dose-dependent manner in stomach, duodenum, ileum, and colorectal tissue; at equimolar doses, the order of inhibition is FUrd > FUra > FdUrd.

Incorporation of [6-³H]FUrd, [6-³H]FUra, and [6-³H]FdUrd into RNA is dose related and at equimolar doses is greatest after FUrd and least after FdUrd. The relationship between the specific activities of RNA for each drug in any tissue changes with dose. A relationship between the incorporation of the drug into RNA and inhibition of [³H]dThd utilization exists that is independent of the parent drug administered.

FdUMP concentrations were highest after FUra administration in each tissue over the dose range examined (0.09 to 3.08 mmol/kg). In ileum and colorectal tissue, the FdUMP concentration was higher after FdUrd administration than after that of FUrd.

The data indicate that toxicity in these mouse tissues is due to the incorporation of fluorinated pyrimidine into RNA and cannot be correlated with levels of FdUMP. At a specific level of toxicity (50% lethal dose), the ratio for the specific activity of RNA in gastrointestinal tissues (FUrd:FUra:FdUrd) was 1:1.4:1, whereas the ratio found in FdUMP, when FUrd, FUra, and FdUrd were given, was 1:8:11, respectively.

¹ This work was supported by Grants CA21677 and CA23944 from the National Cancer Institute and by the American Lebanese Syrian Associated Charities.

² To whom requests for reprints should be addressed at St. Jude Children's Research Hospital, P. O. Box 318, Memphis, Tenn. 38101.

Received 10/23/78. Accepted 3/20/79.